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| United States Patent |
6,004,577
|
|
Murdock
|
December 21, 1999
|
Enhanced electrotransport of therapeutic agents having polybasic anionic
counter ions
Abstract
Improved electrotransport of therapeutic agents which include agent cations
and polybasic anionic counterions. Improved electrotransport is obtained
by treating the therapeutic agent with a multivalent metal compound of the
formula MX where M is a metallic cation having a valency of at least +2
and is reactive with the polybasic anionic counter ion and X is a
pH-increasing anion. Reduction in species which compete with the
therapeutic agent for electrotranport is obtained.
| Inventors:
|
Murdock; Thomas O. (3999 Clover Ave., Vadnais Heights, MN 55127)
|
| Appl. No.:
|
909678 |
| Filed:
|
August 12, 1997 |
| Current U.S. Class: |
424/443; 424/400; 424/448; 424/449; 514/318; 514/772; 514/788 |
| Intern'l Class: |
A61K 009/70 |
| Field of Search: |
424/400,443,448,449
514/772,788,318
604/20
128/172.1
|
References Cited
U.S. Patent Documents
| 3991755 | Nov., 1976 | Vernon et al. | 128/172.
|
| 4141359 | Feb., 1979 | Jacobsen et at. | 128/172.
|
| 4250878 | Feb., 1981 | Jacobsen et al. | 128/207.
|
| 4383529 | May., 1983 | Webster | 604/20.
|
| 4398545 | Aug., 1983 | Wilson | 128/798.
|
| 4474570 | Oct., 1984 | Ariura et al. | 604/20.
|
| 4722726 | Feb., 1988 | Sanderson et al. | 604/20.
|
| 4731049 | Mar., 1988 | Parsi | 604/20.
|
| 4767401 | Aug., 1988 | Seiderman | 604/20.
|
| 4871352 | Oct., 1989 | Tran | 604/82.
|
| 4886489 | Dec., 1989 | Jacobsen et al. | 604/20.
|
| 4927408 | May., 1990 | Weinshenker et al. | 604/20.
|
| 5068226 | Nov., 1991 | Weinshenker et al. | 514/58.
|
| 5080646 | Jan., 1992 | Theeuwes et al. | 604/20.
|
| 5085749 | Feb., 1992 | Grimshaw et al. | 204/182.
|
| 5147296 | Sep., 1992 | Theeuwes et al. | 604/20.
|
| 5169382 | Dec., 1992 | Theeuwes et al. | 604/20.
|
| 5169383 | Dec., 1992 | Gyory et al. | 604/20.
|
| 5298017 | Mar., 1994 | Theeuwes et al. | 604/20.
|
| 5443442 | Aug., 1995 | Phipps et al. | 604/20.
|
| Foreign Patent Documents |
| 0 449 463 A2 | Oct., 1991 | EP | .
|
| 410009 | Oct., 1933 | DE.
| |
| WO96/02232 A1 | Feb., 1996 | WO | .
|
Other References
Thysman, et al., Anesth Anbalg. 1993; 77:61-66, "In Vivo Iontophoresis of
Fentanyl and Sufentanil in Rats: Pharmacokinetics and Acute Antiociceptive
Effects.".
Lux, H.D., Neuropharmacology. 1974. 13. pp. 509-517, "Fast Recording Ion
Specific Microelectrodes: Their Use in Pharmacological Studies in the
CNS.".
Orlov, et al., Moscow VESTNIK AKADEMI MEDITSINSKIKH NAUK SSSR in Russian
No. 7, 1974, pp.27-31, "Specificity of Neurochemical Mechanisms of
processing Nociceptive Stimulation of Neurons of Difference Structures of
the Rabbit Brain." (English and Russian Version).
|
Primary Examiner: Dees; Jose' G.
Assistant Examiner: Shelborne; Kathryne E.
Claims
I claim:
1. A method of delivering a therapeutic agent through a body surface using
electrotransport wherein the therapeutic agent comprises an agent cation
and a polybasic counter ion, the method comprising the steps of:
providing a solution of the therapeutic agent and a compound, the compound
comprising a metal cation, M and a pH-increasing anion X, M having a
valency of at least +2 and being capable of complexing with said polybasic
anion;
placing the solution in therapeutic agent-transmitting relation to a body
surface; and
delivering the therapeutic agent through the body surface using
electrotransport.
2. The method of claim 1, wherein the compound has the formula:
MX
wherein:
M is selected from the group consisting of aluminum, calcium, cobalt,
copper, iron, nickel, titanium and zinc; and
X is selected from the group consisting of oxide, hydroxide, carbonate,
alkoxide, alkyl, hydrides, acetonylacetonate and mixed
acetonylacetonate-alkoxide.
3. The method of claim 1, wherein M is selected from the group consisting
of calcium, zinc and aluminum, and X is selected from the group consisting
of hydroxide and oxide.
4. The method of claim 1, wherein adding compound MX to the solution raises
solution pH at least 2 pH units.
5. The method of claim 4, wherein adding compound MX to the solution raises
solution pH to a level at which permselectivity of the body surface to
electrotransport flux of the therapeutic agent is enhanced.
6. The method of claim 1, wherein the body surface is skin and the solution
has a pH in the range of about 5 to about 7.
7. The method of claim 1, wherein said polybasic anionic counter ion is
selected from the group consisting of citrate, oxalate, malonate,
succinate, glutarate, adipate, pimelate, maleate, polyacrylate,
polymethacrylate, polyacrylamidomethanesulfonate, fumarate, and mixtures
thereof.
8. The method of claim 1, wherein said polybasic anionic counter ion is
citrate.
9. The method of claim 1, wherein the compound is added to the solution in
an amount which substantially minimizes the concentration of non-complexed
M in solution.
10. The method of claim 1, wherein said therapeutic agent is a citrate drug
salt.
11. The method of claim 1, wherein complexation of the metal cation M with
the polybasic anionic counter ion has a complex formation constant which
is greater than about 1.times.10.sup.4.
12. The method of claim 1, wherein the solution comprises an aqueous
solution.
13. A donor reservoir for an electrotransport device which delivers a
therapeutic agent through a body surface, the donor reservoir containing a
solution comprising:
a therapeutic agent to be delivered wherein the agent comprises an agent
cation and a polybasic anionic counter ion; and
a compound wherein the compound comprises a metal cation M having a valency
of at least +2 and a pH-increasing anion X, the cation M being capable of
complexing with the polybasic anionic counter-ion.
14. The donor reservoir of claim 13, wherein the compound has the formula:
MX
wherein:
M is selected from the group consisting of aluminum, calcium, cobalt,
copper, iron, nickel, titanium and zinc; and
X is selected from the group consisting of oxide, hydroxide, carbonate,
alkoxide, alkyl, hydrides, acetonylacetonate and mixed
acetonylacetonate-alkoxide.
15. The donor reservoir of claim 14, wherein MX is zinc oxide.
16. The donor reservoir of claim 13, wherein the compound is added to the
reservoir in order to raise its pH.
17. The donor reservoir of claim 16, wherein the reservoir pH is in the
range where the permselectivity of the body surface to electrotransport
flux of the therapeutic agent is enhanced.
18. The donor reservoir of claim 16, wherein the body surface is skin and
the reservoir pH is in the range of about 5 to about 7.
19. The donor reservoir of claim 16, wherein said polybasic anionic counter
ion is selected from the group consisting of citrate, oxalate, malonate,
succinate, glutarate, adipate, pimelate, maleate, polyacrylate,
polymethacrylate, polyacrylamidomethanesulfonate, fumarate, and mixtures
thereof.
20. The donor reservoir of claim 13, wherein said polybasic anionic counter
ion is citrate.
21. The donor reservoir of claim 13, wherein a stoichiometric amount of
said compound is added to the donor solution.
22. The donor reservoir of claim 13, wherein said therapeutic agent is a
citrate drug salt.
23. The donor reservoir of claim 13, wherein the complexation of the metal
cation M with the polybasic anionic counter ion has a complex formation
constant which is greater than 1.times.10.sup.4.
24. The donor reservoir of claim 13, wherein the reservoir comprises an
aqueous solution of the therapeutic agent.
25. The donor reservoir of claim 13, wherein the reservoir comprises a
matrix which contains a solution of the therapeutic agent.
26. The donor reservoir of claim 25, wherein the matrix comprises a
hydrophilic polymer.
27. An electrotransport therapeutic agent delivery device comprising the
donor reservoir of claim 13.
28. An amine drug complex of the formula:
##STR5##
wherein R.sub.1 and R.sub.2 may be the same or different and are selected
from the group consisting of H, --OH, lower alkyl, carboxyl, or alkoxy;
R.sub.3 is selected from the group consisting of --H, --OH, lower alkyl or
alkoxy;
R.sub.4 and R.sub.5 may be the same or different and are selected from the
group consisting of --H, --OH, alkyl, lower alkyl, alkoxy, or carboxyl and
wherein Y is selected from the group consisting of fentanyl, sufentanil,
or alfentanyl, M is a metallic cation, and n is an integer having a value
of two or greater.
29. An amine drug complex according to claim 28 wherein the formation
constant for the metal complex is greater than 1.times.10.sup.4.
30. A composition of an amine drug complex of formula:
##STR6##
wherein M is a metallic cation selected from the group consisting of
aluminum, calcium, cobalt, copper, iron, nickel, titanium and zinc, Y is
fentanyl, sufentanil or alfentanil; and wherein the formation constant for
the metal complex is greater than 1.times.10.sup.4.
Description
TECHNICAL FIELD
The invention relates generally to improved electrotransport drug delivery
methods. More specifically, this invention relates to methods for
improving the flux of therapeutic agents having polybasic anionic counter
ions which are iontophoretically delivered.
BACKGROUND OF THE INVENTION
Transdermal delivery of drugs or therapeutic agents is an important
medicament administration route. Transdermal drug delivery bypasses
gastrointestinal degradation and hepatic metabolism, while at the same
time providing slow, but controlled, systemic delivery of a drug or an
agent to a patient's blood stream. It is an especially attractive
administration route for drugs or agents with a narrow therapeutic index,
short half-life and potent activity.
Transdermal permeation of most compounds is a passive diffusion process.
The maximum flux of agent through a patient's skin, i.e., the quantity of
agent delivered through a given area of skin, is primarily determined by
the drug's partition coefficient and solubility characteristics.
Transdermal permeation, however, can be enhanced by iontophoresis.
Iontophoresis is a process by which the transdermal transport of
therapeutic agents or drug is increased or controlled using
electro-repulsion as the driving force. By the application of an external
electrical field to, e.g., an agent-containing reservoir of an
electrotransport device, drugs or agents of like charge are driven by
repulsive forces through the skin. As such, the transdermal delivery
becomes a more controllable, rather than a passive, process, and agent or
drug transport flux is thereby increased.
Iontophoretic devices have been known since the early 1900's. A 1934
British Patent Specification No. 410,009 describes a portable
iontophoretic device which overcame one of the disadvantages of earlier
devices, namely that the patient needed to be immobilized near the current
source. More recently, a number of United States patents have issued in
the iontophoresis field, indicating a renewed interest in this mode of
drug delivery. For example, Vernon et al., U.S. Pat. No. 3,991,755;
Jacobsen et al., U.S. Pat. No. 4,141,359; Wilson, U.S. Pat. No. 4,398,545;
and Jacobsen, U.S. Pat. No. 4,250,878, disclose examples of iontophoretic
devices and some applications thereof.
In presently known iontophoresis devices, at least two electrodes are used.
Both of these electrodes are disposed so as to be in intimate electrical
contact with some portion of the skin of the body. One electrode, called
the "active" or donor electrode, is the electrode from which the ionic (or
ionizable) agent, drug precursor or drug is delivered into the body via
the skin by iontophoresis. The other electrode, called the counter or
return electrode, serves to close the electrical circuit through the body.
In conjunction with the patient's skin contacted by the electrodes, the
circuit is completed by connection of the electrodes to a source of
electrical energy, e.g., a battery.
Depending upon the electrical charge of the species to be delivered
transdermally, either the anode or cathode may be the "active" or donor
electrode. If, for example, the ionic substance to be driven into the body
is positively charged, then the anode will be the active electrode and the
cathode will serve to complete the circuit. On the other hand, if the
ionic substance to be delivered is relatively negatively charged, then the
cathodic electrode will be the active electrode and the anodic electrode
will be the counter electrode.
Alternatively, both the anode and the cathode may be used to deliver drugs
of appropriate charge into the body. In such a case, both electrodes are
considered to be active or donor electrodes. For example, the anodic
electrode can drive positively charged substances into the body while the
cathodic electrode can drive negatively charged substances into the body.
Existing iontophoresis devices generally require a reservoir or source of
the ionized or ionizable species (or a precursor of such species) which is
to be iontophoretically delivered or introduced into the body. Examples of
such reservoirs or sources of ionized or ionizable species include a pouch
as described in the previously mentioned Jacobsen, U.S. Pat. No.
4,250,878, a pre-formed gel body as disclosed in Webster, U.S. Pat. No.
4,382,529, and a generally conical or domed molding of Sanderson et al.,
U.S. Pat. No. 4,722,726. Such drug reservoirs are electrically connected
to the anode or to the cathode of an iontophoresis device to provide a
fixed or renewable source of one or more desired species or agents.
More recently, iontophoretic delivery devices have been developed in which
the donor and counter electrode assemblies have a "multi-laminate"
construction. In these devices, the donor and counter electrode assemblies
are each formed by multiple layers of (usually) polymeric matrices. For
example, Parsi, U.S. Pat. No. 4,731,049, discloses a donor electrode
assembly having hydrophilic polymer based electrolyte reservoir and drug
reservoir layers, a skin-contacting hydrogel layer, and optionally one or
more semipermeable membrane layers. In addition, Ariura et al., U.S. Pat.
No. 4,474,570, discloses a device wherein the electrode assemblies include
a conductive resin film electrode layer, a hydrophilic gel reservoir
layer, and aluminum foil conductor layer and an insulating backing layer.
Hydrogels have been particularly favored for use as the drug reservoir
matrix and electrolyte reservoir matrix in iontophoretic delivery devices,
in part, due to their high equilibrium water content and their ability to
quickly absorb water. In addition, hydrogels tend to have good
biocompatibility with the skin and with mucosal membranes.
Iontophoresis has been used for both the local and systemic delivery of
drugs. The iontophoresis process has been useful in the transdermal
administration of any number of medicaments or drugs. The control of
electrical factors, such as intensity, profile and duration of electrical
current application, as well as physicochemical factors, such as the pH or
ionic strength, allows one to modulate the rate and the duration of
permeation. As intended herein, the particular therapeutic agent to be
delivered may be completely charged (i.e., 100% ionized), completely
uncharged, or partly charged and partly uncharged. The therapeutic agent
or species may be delivered by electromigration, electroosmosis or a
combination of the two. Electroosmosis, in general, results from the
migration of solvent, in which the species is contained, as a result of
the application of electromotive force to the therapeutic species
reservoir.
Of particular interest is the transdermal delivery of analgesic drugs for
the systemic management of moderate to severe pain. Control of the rate
and duration of drug delivery is particularly important for systemic
transdermal delivery of analgesic drugs to avoid the potential risk of
overdose and the discomfort of an insufficient dosage.
One class of analgesics that has found application in a transdermal
delivery route is the synthetic opiates, a group of 4-aniline piperidines.
The synthetic opiates, e.g., fentanyl and certain of its derivatives such
as sufentanil and alfentanyl, are particularly well-suited for transdermal
administration. These synthetic opiates are characterized by their rapid
onset of analgesia, high potency, and short duration of action. They are
estimated to be 80 and 800 times, respectively, more potent than morphine.
These drugs, in the form utilized, are weak bases, i.e., amines, whose
major fraction is cationic in acidic solution. Further, these drugs or
agents have polybasic anionic counter ions e.g, citrate, tartrate, and
maleate.
The amine drugs preferably used in this invention are available
pharmaceutically as citrates, e.g., fentanyl citrate, sufentanil citrate.
In vitro and in vivo studies of iontophoretic delivery of these analgesic
citrates have been reported. See, e.g., Thysman and Preat, Anesth. Analg.,
vol. 77 (1993) 61-66. In an in vivo study to determine plasma
concentration, Thysman and Preat compared simple diffusion of fentanyl and
sufentanil to iontophoretic delivery in citrate buffer at pH 5. Simple
diffusion did not produce any detectable plasma concentration. The plasma
levels attainable depended on the maximum flux of the drug that can cross
the skin and the drug's pharmacokinetic clearance variables. Iontophoretic
delivery was reported to have a significantly reduced lag time (i.e., time
required to achieve peak plasma levels) as compared to passive transdermal
patches (1.5 h versus 14 h). Thus, active electrotranstophoretic delivery
of drugs over passive delivery of these drugs, many issues remain. For
example, fentanyl, in acidic solution exists as the cation FH.sup.+ where
F represents fentanyl. Fentanyl citrate, a pharmaceutically available form
of fentanyl having a polybasic citrate anion, appears to involve only one
of the three carboxylic acid groups of citric acid in salt formation with
the fentanyl. At the pH for optimized permselectivity of skin, namely,
pH.congruent.6.0, the remaining two carboxylic acid groups are ionized and
the protons (H.sup.+) generated in ionization compete with FH.sup.+ for
delivery in the electrotransport process. This competition reduces the
overall efficiency of delivery of FH.sup.+ agent.
Previous work has involved the neutralization of fentanyl citrate with
bases such as sodium or potassium hydroxide. It has been found that such
neutralizations of fentanyl citrate with sodium or potassium hydroxide,
achieve little more than introducing another small monovalent cation
which, similar to protons, competes with fentanyl cation for delivery
during an electrotransport process.
To date, the art has not adequately responded with a solution to this
problem of reducing competitive ions in the electrotransport process.
SUMMARY OF THE INVENTION
The present invention provides an improved electrotransport device and
method for delivering a therapeutic agent through a body surface by
electrotransport where the therapeutic agent comprises, in solution, an
agent cation and a polybasic anionic counter ion. The electrotransport
device comprises a donor reservoir containing a solution of the
therapeutic agent to be delivered and a compound, the compound in solution
forming a metal cation M and a pH-increasing anion X, the metal cation M
having a valency of at least +2 and being reactive with said polybasic
anionic counter ion to form a complex. The method comprises placing the
solution in therapeutic agent-transmitting relation to a body surface and
delivering the therapeutic agent through the body surface by
electrotransport.
A further aspect of the present invention is a method for adjusting the pH
of a solution of a therapeutic agent in a donor reservoir of an
electrotransport delivery device. The method comprises placing, in the
solution of the therapeutic agent, a multivalent metal compound of the
formula:
MX (I)
wherein:
M is a metallic cation having a valency of at least +2 and being reactive
with said polybasic anionic counter ion to form a complex, and X is a
pH-increasing anion.
M is preferably selected from the group consisting of aluminum, calcium,
cobalt, copper, iron, nickel, titanium and zinc. X is preferably selected
from the group consisting of oxide, hydroxide, carbonate, alkoxide, alkyl,
hydrides, acetonylacetonate and mixed acetonylacetonate-alkoxide. Most
preferred are those compounds of formula I in which M is calcium, zinc or
aluminum, and X is oxide or hydroxide. The therapeutic agent is preferably
a salt, is more preferably an amine, and is most preferably is an amine
salt selected from the group consisting of fentanyl citrate, sufentanil
citrate and alfentanil citrate.
In another aspect, the present invention is an amine drug complex of the
formula:
##STR1##
wherein R.sub.1 and R.sub.2 may be the same or different and are selected
from the group consisting of --H, --OH, lower alkyl, carboxyl, or alkoxy;
R.sub.3 is selected from the group consisting of --H, --OH, lower alkyl or
alkoxy; R.sub.4 and R.sub.5 may be the same or different and are selected
from the group consisting of --H, --OH, alkyl, lower alkyl, alkoxy, or
carboxyl; Y is the amine drug to be delivered; M is a metallic cation; and
n is an integer having a value of two or greater. Preferably, the
formation constant for the amine complex of formula (II) is
1.times.10.sup.4.
In a preferred aspect, the invention is a complex of the formula:
##STR2##
wherein M is a metallic cation selected from the group consisting of
aluminum, calcium, cobalt, copper, iron, nickel, titanium and zinc; Y is
fentanyl, sufentanil or alfentanil; n is an integer of value 2 or greater
and wherein the formation constant for the metal complex (III) is greater
than about 1.times.10.sup.4. The preferred complex of formula (III) has
R.sub.1, R.sub.2, R.sub.4, and R.sub.5 of formula (II) comprising hydrogen
(--H) and R.sub.3 comprising hydroxyl (--OH).
In yet further aspect, the invention provides a drug reservoir for an
iontophoresis device. The reservoir includes an agent to be delivered
iontophoretically, a hydrogel disc saturated with the agent, having
opposite sides, and a multivalent metal compound of formula (I) layered on
one side of the hydrogel disc. The agent to be delivered is fentanyl,
sufentanil or alfentanil, and is suitably in the form of a salt of a
polycarboxylic acid. Alternatively, the hydrogel disc contains both the
agent salt and the metal compound of formula (I). The hydrogel disc may
comprise essentially any suitable hydrogel. Preferably, the disc comprises
a hydrogel selected from the group consisting of synthetic polymers such
as poly(acrylamide), poly(2-hydroxyethyl acrylate), poly(2-hydroxypropyl
acrylate), poly(N-vinyl-2-pyrrolidone), poly(n-methylol acrylamide),
poly(diacetone acrylamide), poly(2-hydroxyethyl methacrylate), poly(vinyl
alcohol), and poly (allyl alcohol). Hydroxyl functional condensation
polymers (i.e., polyesters, polycarbonates, polyurethanes) are also
examples of suitable synthetic polymers. Naturally occurring polymers (or
derivatives thereof suitable for use as the gel matrix are exemplified by
cellulose ethers, methyl cellulose ethers, cellulose and hydroxylate
cellulose, methyl cellulose and hydroxylated methyl cellulose, gums such
as guar, locust, karaya, xanthan, gelatin and derivatives thereof.
In yet another aspect, the invention provides an iontophoretic device. The
device includes a donor electrode including a drug reservoir; a counter
electrode; and an electrical energy source electrically connected to the
donor electrode and the counter electrode. The drug reservoir includes an
agent to be delivered iontophoretically, a hydrogel disc saturated with
the agent, having opposite sides, and a multivalent metal compound of
formula (I) layered on one side of the hydrogel disc. The agent to be
delivered is fentanyl, sufentanil or alfentanil, and is in the form of a
salt of a polycarboxylic acid. Alternatively, the hydrogel disc contains
both the agent salt and the metal compound of formula (I). The hydrogel
disc comprises a hydrogel as was described above. The multivalent metal
compound is also described above and preferably comprises a compound of
formula (I).
As used herein, the term "treating" should be broadly construed to include,
but not be limited to, "reacting," "precipitating," "complexing,"
"chelating" and "mixing."
As used herein the term "polybasic anionic counter ion" is intended to
mean, with exemplary reference to carboxylic acids, any carboxylic acid
having two or more hydrogen atoms available for salt formation. Di-, tri-
and tetracarboxylic acids (and higher) are contemplated by this invention
but should not be construed as limiting thereof. For example, and without
limitation, this term contemplates within its scope, polyacrylic acid,
polymethacrylic acid, and generally, any polycarboxylic acid. Another
family of polybasic anionic counter ion would be the copolymers of
styrene/maleic acid. One skilled in the art will be able to apply this
definition to other chemical species.
As used herein and generally used in the art, the terms "polydentate" or
"bidentate" refer to the number of coordinate bonds that a single ligand
forms with a metal ion. Those terms are largely synonymous with the term
"polybasic" as defined above.
Other advantages and a fuller appreciation of specific adaptations,
compositional variations, and physical attributes of the present invention
will be gained upon an examination of the following drawings, detailed
description of preferred embodiments, and appended claims. It is expressly
understood that the drawings are for the purpose of illustration and
description only, and are not intended as a definition of the limits of
the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
The preferred exemplary embodiment of the present invention will
hereinafter be described in conjunction with the appended drawing in
which:
FIG. 1 is an exploded view of an electrotransport drug delivery device in
accordance with the present invention.
MODES FOR CARRYING OUT THE INVENTION
The present invention relates broadly to improved methods for the
iontophoretic delivery of therapeutic agents and to a delivery system
therefor. More specifically, the present invention is particularly
well-adapted for the administration, by electrotransport delivery, of
certain drugs or therapeutic agents. The preferred therapeutic agents in a
practice of this invention are basic, are preferably amines, and most
preferably as fentanyl and related species as was described above.
Accordingly, the present invention will now be described in detail with
respect to such preferred species. However, those skilled in the art will
appreciate that such a description of the invention is meant to be
exemplary only and should not be viewed as limitative of the full scope
thereof.
In one of its aspects, the present invention is a method for increasing
flux in iontophoretic drug delivery of an amine drug salt or amine
therapeutic agent. Amine drug salts for treatment in accordance with a
preferred practice of the present invention are selected from the
synthetic opiates of the 4-aniline piperidine group. Like many therapeutic
agents, these compounds exist as cations in aqueous solution. These
synthetic opiates are pharmaceutically available as citrate salts.
Preferred synthetic opiates in accordance with this invention are the
amine citrate salts of e.g., fentanyl citrate, sufentanil citrate and
alfentanil citrate.
An aqueous solution of fentanyl citrate (20 mg of free fentanyl base/ml)
has a pH of about 3.8. It has been found that if amine salts are treated,
i.e., neutralized, with a multivalent metal compound such as an oxide or a
hydroxide, e.g., zinc oxide or calcium hydroxide, the pH is increased and
the electrotransport of the drug cation is increased. Addition of a
stoichiometric amount of the metal compound (i.e., addition of 1 mole of
metal compound/mole of citrate anion) increases the pH to about 5 to 6,
the optimal pH for permselectivity of skin.
In amine citrate salts such as fentanyl citrate, only one of the carboxylic
acid groups of the citric acid is involved in salt formation with the
opiate amine. The two remaining carboxylic acid groups are ionized and the
protons compete with the fentanyl cation, FH.sup.+, for electrotransport.
However, polycarboxylic acids, such as citric acid, act also as
polydentate ligands, i.e., the carboxylic acid groups act as ligands.
Generally, multivalent metal ions bond strongly to polydentate ligands.
Therefore, without intending to be bound by theory, a proposed mechanism
for the results achieved by the method of the present invention is that
reaction of the carboxylic acid groups with multivalent metal bases
results in complexation between the metal ion and the carboxylate groups,
i.e., the acid groups act as a bidentate ligand to complex the metal ion.
Such neutralization/complexation is given by the following equation which
illustrates fentanyl citrate as the salt and zinc oxide as the multivalent
metal base compound:
##STR3##
In such a reaction, the concentration of the multivalent metal ion in
aqueous solution is greatly diminished compared to noncomplexing metal
ions such as sodium or potassium wherein sodium or potassium hydroxides
are used to neutralize the acid groups. If the metal ion concentration in
solution is negligible, then the electrotransport of the fentanyl cation
will not be decreased.
The stability of metal complexes with ligands is described by the formation
constant, K.sub.1 which provides a measure of the equilibrium between the
complexed and uncomplexed metal ions as illustrated below.
M.sup.n+ +L.sup.3- .revreaction.ML.sup.+n-3
where M.sup.n+ is the metal cation, as described hereinabove, and L is a
ligand with -3 charge such as citrate. The formation constant K is,
therefore,
##EQU1##
If K for the complexing of the metal ion with a ligand is large, then the
concentration of the metal ion in solution is small. In this instance, the
metal ions in accordance with the present invention are strongly bound to
the two carboxylate groups of, e.g., fentanyl citrate. Therefore, the
concentration of free metal ion resulting from complexation with the amine
salt drug is typically <0.05 mM (or less than about 0.01% of the
therapeutic agent) and the formation constant K is in the range of about
1.times.10.sup.+4 to about 1.times.10.sup.-8 or greater.
In another aspect, the present invention is a composition of an amine drug
that provides enhanced iontophoretic delivery of the amine drug, in an
aqueous medium, to a subject. The composition comprises, in aqueous
medium, the complex of formula:
##STR4##
wherein YH.sup.+ is a cation drug selected from the group consisting of
fentanyl, sufentanil and alfentanil; M is a multivalent metal ion selected
from the group consisting of aluminum, calcium, cobalt, copper, iron,
nickel, titanium and zinc; n is an integer of value 2 or greater and
wherein the formation constant for the M--COO.sup.- bond is greater than
1.times.10.sup.4. Preferred are those compositions of formula (III)
wherein M is zinc, calcium and aluminum, and the pH of the complex of
formula (III) in aqueous medium is about 5 to 6.
Complex formation and improved electrotransport was first confirmed by
model compound studies in which N-methylpiperidine, a compound
structurally similar to fentanyl, was reacted with the compounds of
formula (I). The infrared (IR) spectrum of N-methylpiperidine citrate was
compared with the IR spectrum of a complex formed by addition of a
stoichiometric amount of zinc oxide to an aqueous solution of
N-methylpiperidine citrate. The IR spectrum was consistent with the
derived compound and distinctly different from that of zinc citrate and
N-methylpiperidine citrate.
Improved electrotransport for opiate amine citrates has been demonstrated
in accordance with the present invention. Fentanyl citrate, neutralized
with compounds of formula (I), was provided in an electrotransport device
and the electrotransport flux measured. It has been found that treatment
with the metal compound of formula (I) improves the electrotransport flux
(.mu.g/cm.sup.2 -hr) of fentanyl by between about 25% to about 150%.
It will be appreciated by those working in the field that the present
method can be used in conjunction with a wide variety of electrotransport
drug delivery systems, as the method is not limited in any way in this
regard. For examples of electrotransport drug delivery systems, reference
may be had to U.S. Pat. Nos. 5,147,296 to Theeuwes et al., 5,080,646 to
Theeuwes et al., 5,169,382 to Theeuwes et al., and 5,169,383 to Gyory et
al., the disclosures of which are incorporated by reference herein.
FIG. 1 illustrates a representative electrotransport delivery device that
may be used in conjunction with the present method. Device 10 comprises an
upper housing 16, a circuit board assembly 18, a lower housing 20, anode
electrode 22, cathode electrode 24, anode reservoir 26, cathode reservoir
28 and skin-compatible adhesive 30. Upper housing 16 has lateral wings 15
which assist in holding device 10 on a patient's skin. Upper housing 16 is
preferably composed of an injection moldable elastomer (e.g., ethylene
vinyl acetate). Printed circuit board assembly 18 comprises an integrated
circuit 19 coupled to discrete components 40 and battery 32. Circuit board
assembly 18 is attached to housing 16 by posts (not shown in FIG. 1)
passing through openings 13a and 13b, the ends of the posts being
heated/melted in order to heat stake the circuit board assembly 18 to the
housing 16. Lower housing 20 is attached to the upper housing 16 by means
of adhesive 30, the upper surface 34 of adhesive 30 being adhered to both
lower housing 20 and upper housing 16 including the bottom surfaces of
wings 15.
Shown (partially) on the underside of circuit board assembly 18 is a button
cell battery 32. Other types of batteries may also be employed to power
device 10.
The device 10 is generally comprised of battery 32, electronic circuitry
19, 40, electrodes 22, 24, and drug/chemical reservoirs 26, 28, all of
which are integrated into a self-contained unit. The outputs (not shown in
FIG. 1) of the circuit board assembly 18 make electrical contact with the
electrodes 24 and 22 through openings 23, 23' in the depressions 25, 25'
formed in lower housing 20, by means of electrically conductive adhesive
strips 42, 42'. Electrodes 22 and 24, in turn, are in direct mechanical
and electrical contact with the top sides 44', 44 of drug reservoirs 26
and 28. The botton sides 46', 46 of drug reservoirs 26, 28 contact the
patient's skin through the openings 29', 29 in adhesive 30.
Device 10 optionally has a feature which allows the patient to
self-administer a dose of drug by electrotransport. Upon depression of
push button switch 12, the electronic circuitry on circuit board assembly
18 delivers a predetermined DC current to the electrodes/reservoirs 22, 26
and 24, 28 for a delivery interval of predetermined length. The push
button switch 12 is conveniently located on the top side of device 10 and
is easily actuated through clothing. A double press of the push button
switch 12 within a short time period, e.g., three seconds, is preferably
used to activate the device for delivery of drug, thereby minimizing the
likelihood of inadvertent actuation of the device 10. Preferably, the
device transmits to the user a visual and/or audible confirmation of the
onset of the drug delivery interval by means of LED 14 becoming lit and/or
an audible sound signal from, e.g., a "beeper". Drug is delivered through
the patient's skin by electrotransport, e.g., on the arm, over the
predetermined delivery interval.
Anodic donor electrode 22 is preferably comprised of silver and cathodic
counter electrode 24 is preferably comprised of silver chloride. Both
reservoirs 26 and 28 are preferably comprised of polymer hydrogel
materials. Electrodes 22, 24 and reservoirs 26, 28 are retained by lower
housing 20.
The push button switch 12, the electronic circuitry on circuit board
assembly 18 and the battery 32 are adhesively "sealed" between upper
housing 16 and lower housing 20. Upper housing 16 is preferably composed
of rubber or other elastomeric material. Lower housing 20 is preferably
composed of a plastic or elastomeric sheet material (e.g., polyethylene)
which can be easily molded to form depressions 25, 25' and cut to form
openings 23, 23'. The assembled device 10 is preferably water resistant
(i.e., splash proof) and is most preferably waterproof. The system has a
low profile that easily conforms to the body, thereby allowing freedom of
movement at, and around, the wearing site. The reservoirs 26 and 28 are
located on the skin-contacting side of the device 10 and are sufficiently
separated to prevent accidental electrical shorting during normal handling
and use.
The device 10 adheres to the patient's body surface (e.g., skin) by means
of peripheral adhesive 30 which has upper side 34 and body-contacting side
36. The adhesive side 36 has adhesive properties which assures that the
device 10 remains in place on the body during normal user activity, and
yet permits reasonable removal after the predetermined (e.g., 24-hour)
wear period. Upper adhesive side 34 adheres to lower housing 20 and
retains the electrodes and drug reservoirs within housing depressions 25,
25' as well as retains lower housing 20 attached to upper housing 16.
The reservoirs 26 and 28 generally comprise a gel matrix, with the drug
solution uniformly dispersed in anodic reservoir 26. Drug concentrations
in the range of approximately 1.times.10.sup.-4 M to 1.0 M or more can be
used, with drug concentrations in the lower portion of the range being
preferred. Suitable polymers for the gel matrix may comprise essentially
any synthetic and/or naturally occurring polymeric materials. A polar
nature is preferred when the active agent is polar and/or capable of
ionization, so as to enhance agent solubility. Optionally, the gel matrix
is water swellable. Examples of suitable synthetic polymers include, but
are not limited to, poly(acrylamide), poly(2-hydroxyethyl acrylate), poly
(2-hydroxypropyl acrylate), poly(N-vinyl-2-pyrrolidone), poly(n-methylol
acrylamide), poly(diacetone acrylamide), poly(2-hydroxylethyl
methacrylate), poly(vinyl alcohol) and poly(allyl alcohol). Hydroxyl
functional condensation polymers (i.e., polyesters, polycarbonates,
polyurethanes) are also examples of suitable polar synthetic polymers.
Polar naturally occurring polymers (or derivatives thereof) suitable for
use as the gel matrix are exemplified by cellulose ethers, methyl
cellulose ethers, cellulose and hydroxylated cellulose, methyl cellulose
and hydroxylated methyl cellulose, gums such as guar, locust, karaya,
xanthan, gelatin, and derivatives thereof. Ionic polymers can also be used
for the matrix provided that the available counterions are either drug
ions or other ions that are oppositely charged relative to the active
agent.
The adjusted pH drug solution of the present invention is incorporated into
the drug reservoir, e.g., a gel matrix as just described, and administered
to a patient using an electrotransport drug delivery system, optionally as
exemplified hereinabove. Incorporation of the drug solution can be done
any number of ways, i.e., by imbibing the solution into the reservoir
matrix, by admixing the drug solution with the matrix material prior to
hydrogel formation, or by imbibing the solution into the reservoir matrix
after formation of the matrix. Alternatively, the drug and compound MX can
be placed in a dry donor reservoir matrix and a liquid solvent (e.g.,
water) is later added to the dry matrix (e.g., at the time of use).
The compound MX is preferably dispersed throughout the donor reservoir 26.
Most preferably, the molar loading of compound MX is about equal to the
molar loading of the therapeutic agent in reservoir 26. By virtue of the
way in which the pH of the formulation is adusted, introduction of
competitive ions or extraneous contaminants is avoided and drug flux is
optimized.
The donor reservoir 26 typically has a skin-contact area in the range of
about 1 cm.sup.2 to about 50 cm.sup.2. Generally speaking, a current in
the range of about 50 to 5000 .mu.A is employed during drug delivery.
As was noted above, the present invention is applicable to the
electrotransport delivery of essentially any therapeutic species
comprising an agent cation and a polybasic anionic counter ion. Examples
of other therapeutic species to which this invention is likely to include,
without limitation, lisuride maleate, loxapine succinate, metaraminol
bitartrate and oxalate dihydrate, epinephrine bitartrate, brovincamine
fumarate, diethylcarbamazine citrate, dimethidene maleate, dextromoramide
tartrate, acepromazine citrate, diethylcarbamazine citrate. Generally
speaking, zinc oxide will be the preferred species MX with which to react
the selected therapeutic agent. One skilled in the art understanding the
full scope of this invention will likely recognize that there are many
further therapeutic species to which this invention may apply.
The present invention is further explained by the following examples which
should not be construed by way of limiting the scope of the present
invention. Process steps described in the examples are carried out at room
temperature and atmospheric pressure unless otherwise specified.
EXAMPLE 1
Demonstration of Neutralization and Complex Formation with Calcium
Hydroxide
A model compound study was initiated to investigate the reaction between an
amine citrate salt and calcium hydroxide, i.e., specifically to evaluate
the ability of calcium hydroxide to adjust the pH of citrate salt
solutions. The amine chosen was N-methylpiperdine because of its
structural similarity to the synthetic opiate agents.
N-methylpiperidinium citrate was prepared by the reaction of citric acid
and N-methylpiperidine in ethanol. Citric acid and ethanol were mixed at
25.degree. C. until completely dissolved. N-methylpiperidine was added
dropwise to the citric acid solution over 5 minutes. The salt was
recrystallized from hot ethanol and the IR spectrum was run and found to
be consistent with the desired compound.
Into 10 ml of an aqueous solution 0.05 mM N-methylpiperidinium citrate were
added (an equimolar amount) 0.37 g of calcium hydroxide. After stirring
the solution at 25.degree. C. for about 5 minutes, a clear solution
formed. A white precipitate formed after approximately 30 minutes. The IR
spectrum of the isolated precipitate matched the spectrum of calcium
citrate. The intermediate where a calcium ion was bound to two acid groups
of the citrate molecule was not isolated. The addition of calcium
hydroxide adjusted the pH of the solution from 3.7 to 6.1. The results
show that calcium hydroxide is useful for adjusting the pH of citrate drug
salts.
EXAMPLE 2
Demonstration of Neutralization and Complex Formation with Zinc Oxide
A similar study was initiated as in Example 1 to evaluate the ability of
ZnO to adjust the pH of an aqueous solution of N-methylpiperidinium
citrate. The addition of zinc oxide yielded slightly different results in
that the reaction did not produce zinc citrate as a precipitate.
N-methylpiperidinium citrate was prepared as described in Example 1. Into a
10 ml of an aqueous solution of 0.05 mM N-methylpiperidinium citrate was
added an equimolar amount (0.005 mol) of zinc oxide. A zinc complex was
isolated by precipitation with isopropyl alcohol and recrystallized from
hot isopropyl alcohol/water. The IR spectrum of the resulting complex was
consistent with the desired product, i.e., the zinc ion bound to the two
acid groups, and distinctly different from the IR spectrum of zinc
citrate. The addition of zinc oxide adjusted the pH of the solution from
3.7 to 5.7. The results show that zinc oxide is useful for adjusting the
pH of citrate drug salts.
EXAMPLE 3
Neutralization and Complex Formation using a Hydrogel Reservoir coated with
Calcium Hydroxide
In this experiment, the pH of hydrogels (suitable as a donor reservoir)
containing N-methylpiperidinium citrate was adjusted with the addition of
calcium hydroxide. Hydrogel discs suitable for use in an electrotransport
device having the following formulation were prepared by techniques known
in the art as follows.
______________________________________
Material % by Weight
______________________________________
Deionized Water 83.5
Non-ionic Guar 0.5
Glycerol 5.0
Mowiol 66-100 10.0
Methocel K100 MP
1.0
______________________________________
N-methylpiperidinium citrate was weighed on a piece of weighing paper and
transferred to the surface of the hydrogel disc. The amine citrate salt,
being very water soluble, diffused into the hydrogel disc in less than
five minutes. These imbibed gel discs were stored in sealed pouches at
5.degree. C. The gel pH was measured after 24 hours. Calcium hydroxide was
spread evenly on one side of the hydrogel discs with a spatula. The pH of
these hydrogels was measured at 72 and 168 hours after the application of
calcium hydroxide. The results are shown in Table 1.
TABLE 1
______________________________________
mol pH @ mg mol pH @ pH @
Gel #
NMP-CT* 24 hrs. Ca(OH).sub.2
Ca(OH).sub.2
72 hrs.
168 hrs.
______________________________________
1 1.18 .times.
4.0 9.06 1.22 .times. 10.sup.-4
5.7 5.8
10.sup.-4
2 1.18 .times.
4.1 6.73 0.91 .times. 10.sup.-4
5.0 5.2
10.sup.-4
3 1.20 .times.
4.1 4.54 0.61 .times. 10.sup.-4
4.6 4.7
10.sup.-4
______________________________________
*NMP-CT = Nmethylpiperidinium citrate
The reaction in the hydrogels correlated with the reactions observed in the
solution of Example 1. As seen from Table 1, the addition of calcium
hydroxide neutralized the pH of the hydrogels. Table 1 also illustrates
that as the molar ratio of metal compound to citrate salt approaches 1:1,
enhanced neutralization occurs. After 7 days a white solid was observed on
the surface of the discs. The solid was a mixture of unreacted calcium
hydroxide and/or calcium citrate.
EXAMPLE 4
Neutralization and Complex Formation using a Hydrogel Reservoir coated with
Zinc Oxide
Hydrogel discs prepared as described in Example 3 were imbibed with
N-methylpiperidinium citrate. The gel pH was measured after storing the
gel in a sealed pouch at 5.degree. C. for 24 hours. Zinc oxide was then
spread evenly on one side of the hydrogel discs with a spatula. The gels
were stored in a sealed pouch for another 24 hours, and the pH was
measured. After six and seven days (i.e., 144 hrs. and 168 hrs. after
application), the pH of the gels was remeasured. The results are shown in
Table 2. No unreacted zinc oxide was observed on the surface of the gels.
TABLE 2
______________________________________
mol pH @ mol ZnO pH @ pH @ pH @
Gel #
NMP-CT 24 hrs. added 24 hrs.
144 hrs.
168 hrs.
______________________________________
1 1.17 .times. 10.sup.-4
3.8 1.20 .times. 10.sup.-4
6.6 5.6 5.3
2 1.18 .times. 10.sup.-4
3.8 0.91 .times. 10.sup.-4
4.4 4.6 4.4
3 1.19 .times. 10.sup.-4
3.8 0.61 .times. 10.sup.-4
4.5 4.4 4.3
______________________________________
The reaction in the hydrogels correlated with the reactions observed in the
solution of Example 2. Zinc oxide reacted with N-methylpiperidinium
citrate and effectively neutralized the hydrogels. Table 2 also
illustrates that as the molar ratio of metal compound to citrate salt
approaches 1:1, enhanced neutralization occurs. The relatively large pH
shift observed in the gel resulted from some of the zinc oxide remaining
unreacted with the N-methylpiperidinium citrate in the gel. As more zinc
oxide reacted, the pH decreased.
EXAMPLE 5
Neutralization and Complex Formation using a Fentanyl imbibed Hydrogel
Hydrogel discs containing either zinc oxide or calcium hydroxide were
prepared from mixtures having the following formulation:
______________________________________
Material % by Weight
______________________________________
Non-ionic Guar 0.5
GIyceroI 5.0
Mowiol 66-100 8.0
Methocel K100 MP
1.0
Cholestyramine 10.0
Zinc Oxide 0.31
or
Calcium Hydroxide
0.28
Deionized Water balance
______________________________________
These hydrogels were imbibed with fentanyl citrate in a 1:1 molar ratio
with the metal compound in the gel. Hydrogels of this formulation without
the metal agents exhibit a pH of 3.8. The addition of calcium hydroxide or
zinc oxide into the hydrogels raised the pH to 5.8.
The hydrogels of this example were then incorporated into electrotransport
devices to assess fentanyl delivery across human epidermis samples. These
systems applied a current of 100 .mu.A through a drug releasing area of 1
cm.sup.2 and the electrotransport flux measuring the results are shown in
Table 3.
TABLE 3
______________________________________
Steady State Summary
Added Metal Avg. Flux
Compound (.mu.g/cm.sup.2 -hr.)
Std. Dev.
______________________________________
None 11.8 2.4
Zinc Oxide 15.2 2.1
Calcium Hydroxide
29.7 4.2
______________________________________
Table 3 shows that at steady state, both zinc oxide and calcium hydroxide
enhance the flux of fentanyl through the skin. However, addition of
calcium hydroxide greatly enhanced the fentanyl flux of the system
compared to a device run under the same conditions without complex
formation.
EXAMPLE 6
Epinephrine bitartrate is dissolved in water to create an aqueous solution.
The epinephrin bitartrate solution is further mixed with zinc oxide.
Addition of zinc oxide to the epinephrin bitartrate solution raises its pH
and creates a complex. The complex exhibits enhanced delivery by
electrotransport.
In summary, the present invention provides a method for improving the
electrotransport of basic, primarily amine drug salts, primarily salts of
the synthetic opiates, by treating, prior to iontophoretic delivery, i.e.,
neutralizing and complexing, the acid groups not involved in salt
formation. The invention also provides an amine metal citrate complex form
of the synthetic opiates that facilitates the electromigration of these
drugs in their cation form. An iontophoretic device using the method of
the invention is also provided.
While the present invention has now been described and exemplified with
some specificity, those skilled in the art will appreciate the various
modifications, including variations, additions, and omissions, that may be
made in what has been described. Accordingly, it is intended that these
modifications also be encompassed by the present invention and that the
scope of the present invention be limited solely by the broadest
interpretation that lawfully can be accorded the appended claims.
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